The aromatase inhibitor 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile, also known as 4-[α-4-Cyanophenyl)-α-fluoro-1-(1,2,4-triazolyl)methyl]-benzonitrile or CGP47645, first described in 1992 [EP 490 816 and U.S. Pat. No. 5,637,605], has the following structural formula (I)

The compound 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile is a crystalline compound with a sharp melting endotherm at 169.5° C. The crystalline powder is not hygroscopic and is poorly soluble in water.
4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile (CGP47645) is a highly specific and potent aromatase inhibitor which was shown here within to have a longer half life in humans than does letrozole (Femara®), a marketed aromatase inhibitor to which CGP47645 is structurally related. In vitro experiments with human placental microsomal aromatase demonstrated an IC50=6 nM. Oral administration of CGP47645 to rats demonstrated a T½ of 75 hours. The exposure expressed as AUC was proportional to the administered dose. In two different aromatase dependent experimental models, inhibition of androstenedione-induced uterine hypertrophy in rats and inhibition of DMBA-induced mammary tumors in rats, the ED50 was 0.003 mg/kg and 0.01 mg/kg, respectively. These results suggested CGP47645 is approximately 10-fold more potent than letrozole.
4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile is a highly potent and cohesive drug which needs to be dispensed in low doses. Such drugs require a careful formulation and production in order to produce solid oral dosage forms with acceptable content uniformity and physical stability. There is a need to formulate 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile into pharmaceutical compositions, especially solid oral dosage forms, such that the therapeutic benefits of the compound may be delivered safely to a patient in need thereof.
Formulation of low dose medicines can be very challenging and problems related to content uniformity and physical stability may arise. Content uniformity is a key parameter for oral solid dosage forms, because significant deviations in active content may impact the performance of the product in terms of efficacy and safety. The selection of the excipients and the specific steps during the manufacturing are critical factors and need to be controlled in order to get a homogenous and segregation-free low dose formulation.
Accordingly, the present invention provides a solid pharmaceutical composition suitable for oral administration, comprising CGP47645.